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Annulation of Non-Conjugated Alkenes Via Directed Nucleopalladation

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Annulation of Non-Conjugated Alkenes Via Directed Nucleopalladation ARTICLE https://doi.org/10.1038/s41467-020-20182-4 OPEN Anti-selective [3+2] (Hetero)annulation of non- conjugated alkenes via directed nucleopalladation Hui-Qi Ni1, Ilia Kevlishvili2, Pranali G. Bedekar1, Joyann S. Barber3, Shouliang Yang3, Michelle Tran-Dubé3, ✉ ✉ ✉ Andrew M. Romine 1, Hou-Xiang Lu1, Indrawan J. McAlpine 3 , Peng Liu 2 & Keary M. Engle 1 2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures 1234567890():,; from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free –NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination. 1 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. 2 Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA. 3 Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, CA 92121, ✉ USA. email: indrawan.mcalpine@pfizer.com; [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:6432 | https://doi.org/10.1038/s41467-020-20182-4 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20182-4 atalytic (hetero)annulation1–4 of C–C π-systems is a that the issues highlighted above could potentially be cir- Cpowerful method for constructing carbocyclic and het- cumvented by engaging an alternative mechanism, namely a erocyclic core structures from comparatively simple pro- sequence of Pd(II)-mediated Wacker-type nucleopalladation, genitor compounds. Of special importance within the modern followed by oxidative addition of the Ar–X bond to form a high- synthetic repertoire is the Pd(0)-catalyzed Larock indole synth- valent Pd(IV) intermediate, and finally C(sp3)–Ar reductive esis, first described in 19915, which unites alkynes and 2- elimination. If successfully developed, such a process would haloanilines (Fig. 1a). Later in 1995 and 2005, the Larock group potentially enable access to net anti-annulation, thereby com- reported analogous methods for benzo[b]furan and indene plementing existing methods, which proceed in a syn-selective synthesis6,7. Mechanistically, such reactions are generally believed fashion. Of relevance to this proposal, the Mazet and Zhang to proceed via oxidative addition, migratory insertion of the groups have described Pd(0)/Pd(II) heteroannulation systems in resultant arylpalladium(II) species, and C(sp2)–N/O/C reductive which syn-oxy/aminopalladation is proposed to take place from a • II 3 – elimination. Ln Pd (Ar)(X) intermediate, such that C(sp ) O/N bond for- While palladium-catalyzed alkyne annulation reactions are well mation precedes C(sp3)–Ar bond formation14–17. developed and widely deployed in preparative chemistry, During the past 5 years, our laboratories have developed a employment of alkenes in analogous processes is comparatively variety of transition-metal-catalyzed, three-component directed rare and limited to activated substrates like styrenes8–10, 1,3- alkene 1,2-difunctionalization reactions facilitated by the 8- dienes11, norbornenes12, and enol ethers/esters13–17 (Fig. 1b). aminoquinoline (AQ) auxiliary, a strongly coordinating biden- Extension of this mode of reactivity to unactivated alkenes has tate directing group. Using this strategy we and others have proven to be challenging for several interrelated reasons: (1) reported examples of hydrofunctionalization21–33, dicarbo- competitive β-hydride elimination following migratory insertion; functionalization34–39, carboamination40,41, and carbo-/amino- (2) inherently challenging C(sp3)–N/O/C reductive elimination18; boration42–45, among other transformations46,47 (Fig. 1c). We and (3) competitive alkene isomerization pathways19. In 2015, the recognized several issues that would need to be addressed to bring Jamison group reported an elegant method to access indolines a directed (hetero)annulation process to fruition: (1) phenols and from unactivated alkenes by taking advantage of nickel/photo- anilines have previously proven to be ineffective coupling part- redox dual catalysis20, though the reaction required use of an N- ners in AQ-directed alkene additions in our hands, leading to the acetyl protecting group and was only demonstrated with terminal hypothesis that nucleopalladation in these cases is endergonic; (2) alkenes, thereby limiting the product structures that can be due to their intramolecular nature, the oxidative addition and accessed. To our knowledge, analogous processes between O- reductive elimination transitions states involving Pd(IV) would based and C-based coupling partners and unactivated alkenes likely be highly strained; and (3) competitive pathways arising remain unknown. from Heck-type or Wacker-type oxidative alkene addition or In order to bridge this important synthetic gap, we sought to hydrofunctionalization could predominate. At the outset, our develop an all-encompassing annulation process that could unite hypothesis was that the presence of an ortho-halogen would allow non-conjugated alkenes and a diverse collection of O-based, N- for rapid trapping of a potentially short-lived nucleopalladated based, and C-based coupling partners. Specifically, we envisioned intermediate. In this work, by employing ambiphilic coupling partners we successfully achieve the (hetero)annulation of AQ-directed non- 48 a Larock-type [3+2] heteroannulation with alkynes conjugated alkenes , thereby providing direct access to useful R3 49–52 I cat. Pd0 2,3-dihydrobenzofurans, indolines, and indanes . Mechanistic + R2 R3 R2 experiments and DFT studies shed light on the origins of dia- NHR1 N R1 stereoinduction, anti-selectivity, and other aspects of this Pd(II)/ Pd(IV) annulation process. b Catalytic [3+2] heteroannulation with alkenes Oxidative addition/ C–X Results syn-migratory insertion Reductive R2 cat. Pd0 elimination Scope of phenols. We began by using AQ-containing alkenyl I X 1 Mn R amide 1a as the model alkene and 2-iodophenol (2aa) as the or R2 X XH cat. NiI / R1 (syn) coupling partner. After brief optimization (see Supplemen- + IrIII + hv tary Information for details), we identified effective conditions Under 2 R2 developed R using Pd(OAc)2 (5 mol%) as the catalyst, K2CO3 (1.0 equiv) as 1 R PdIV the base, and HFIP (1.0 M) as the solvent, at 80 °C, under an air R1 cat. PdII X R2 X atmosphere, allowing for isolation of desired product 3aa in C–C 1 Anti-nucleopalladation/ R Reductive (anti) 96% yield. oxidative addition elimination Having identified a high-yielding and operationally simple c 1,2-Difunctionalization via directed nucleopalladation procedure, we next examined different ortho-iodophenols E O cat. PdII (Table 1). Phenols containing weakly electron-donating groups, Nu AQ t [Nu], [E] namely 4-Me (3ab) and 4- Bu (3ac), furnished the corresponding R (anti) O Nu = C or N products in 85% and 99% yield, respectively. 4-F (3ad), 4-Cl Previous work E = C, B, O, H N (3ae), 4-Br (3af), and 5-Br (3ai) phenols were also well tolerated H R N (AQ) II and gave moderate to high yields, demonstrating the reactions cat. Pd O I X compatibility with various halogen atoms. The presence of AQ strongly electron-withdrawing groups at the 4-position, namely R (anti) XH 4-CO2Me (3ag) and 4-(4-CN-C6H4)(3ah), led to lower yields. This work Fig. 1 Background and project synopsis. a Larock-type [3 + 2] Scope of anilines. Next, we turned to evaluating the aniline scope + heteroannulation with alkynes. b Catalytic [3 2] heteroannulation with (Table 1). With free NH2 anilines, lowering the concentration to alkenes. c 1,2-difunctionalization via directed nucleopalladation. 0.5 M led to higher yields, and substrates with electron- 2 NATURE COMMUNICATIONS | (2020) 11:6432 | https://doi.org/10.1038/s41467-020-20182-4 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20182-4 ARTICLE Table 1 Scope of ortho-iodophenols, ortho-iodoanilines and carbon-based coupling partners. R3 O I cat. Pd(OAc)2, K2CO3 + R3 O AQ XH HFIP, 80 °C, 24 h X AQ (X = O, NH, NR, [C]) 1a 2 3 Phenol Ar–I substitution b CN R X CO2Me Br I O I O O O O O O O AQ O O AQ O O O AQ AQ AQ AQ O AQ 3aa, 96% [X-ray] 3ab, 85% (R = Me, ArI) 3ad, 89% (X = F) n.d. (R = Me, ArBr) 3ae, 75% (X = Cl) 3ag, 49% 3ah, 42% 3ai, 65% 3aj, 30% 3af, 84% (X = Br) 3ac, 99% (R = tBu) Aniline Ar–I substitution CN F OMe MeO2C CO2Me MeO2C O O O O O O HN HN O AQ HN HN HN AQ HN HN AQ AQ AQ AQ AQ 3ba, 75% (ArI) 3bb, 99% 3bc, 73% 3bd, 47% 3be, 76% 3bf, 93% 3bg, 83% 53% (ArBr) Me Me O Me I Br AQ O O O HN O NH2 HN + N HN AQ AQ AQ HN Br AQ AQ O 3bn, 32% 3bn’, 59%f [X-ray] 3bh, 66% (ArBr) 3bi, 47% 3bj, 50% d.r. = 1:1 Lmitations Aniline Het–I substitution Me Me R N N N N N I F N O O O O O HN HN HN NH2 AQ AQ HN AQ HN AQ AQ 2bk, n.r. (R=CO2Me) 2bl, n.r. (R=Me) a a a a 3bo, 85% 3bp, 63% 3bq, 56% 3br, 49% 3bs, 83% 2bm, n.r. (R=Br) Aniline N-substitution OMe O O O O O O TsN AcN N MeN BnN AQ TsN AQ AQ AQ AQ AQ 3bt, >99% 3bu, >99% 3bv, 72%b 3bw, 90% (ArBr) 3bx, 50%c 3by, 58% c Carbon-based coupling partners Limitations I I O O O MeO2C EtO2C EtO2C CO2Me CN MeO2C AQ NC AQ PhO2S AQ 6b, 86%d,f 6c, 62% e,f e e 6a, 96%d 5d, n.r.
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